Methods for the production of ceftobiprole medocaril are known per se. The methods known from the prior art have the common feature that starting from 7-aminocephalosporanic acid, a large number of intermediate stages have to be isolated and purified in order to obtain ceftobiprole medocaril of the general formula (1) in a sufficient purity.
The compound of the general formula (1) is known per se and is described, for example, in WO 99/65920. It can be used for treatment and for prophylaxis of bacterial infectious diseases, in particular infectious diseases which are caused by methicillin-resistant Staphylococcus aureus strains.
WO 99/65920 describes, as the last step of the production process of ceftobiprole medocaril, a reaction in which the medocaril prodrug unit is introduced into a compound of the general formula (2).

The compound of the general formula (2) is likewise known per se and has been described, for example, in EP 0 849 269 A1. According to EP 0 849 269 A1, the production of the compound of the general formula (2) is carried out starting from (2R,6R,7R)-tert-butoxycabonylamino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester by a Wittig reaction with (1′-allyloxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenylphosphonium bromide. The Δ2 reaction product formed in this reaction is isomerized back into the desired Δ3 isomer by sulfoxidation and subsequent reduction, and thereafter deprotected from the benzhydryl ester with trifluoroacetic acid. The acylation in position 7 is carried out by reaction with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)-trityloxyiminothioacetic acid S-benzothiazol-2-yl ester. The compound of the general formula (2) is subsequently obtained by splitting off the protective groups.
EP 1 067 131 A1 describes the formation of the ylide in toluene or a mixture of toluene and methylene chloride by addition of alkali metal tert-butylate in tetrahydrofuran, by which means the base can be added as a solution. The reaction of the ylide with the corresponding aldehyde at a reaction temperature of −70° C. is described.
EP 0 841 339 A1 relates to cephalosporin derivatives and methods for the production thereof. WO 95/29182 likewise discloses intermediate products for the production of cephalosporins.
WO 01/90111 describes a further production of ceftobiprole medocaril in several stages starting from deacetyl-7-aminocephalosporanic acid by acylation with (Z)-(5-amino-[1,2,4]-thiadiazol-3-yl)-trityloxyiminothioacetic acid S-benzothiazol-2-yl ester in N,N-dimethylformamide, followed by in situ esterification with diphenyldiazomethane in methylene chloride to give the corresponding benzhydryl ester, which is precipitated by addition of hexane and isolated. In the next step, this product is oxidized with TEMPO/NaOCl in methylene chloride/water or with manganese dioxide in tetrahydrofuran/methylene chloride to give the corresponding aldehyde. The next reaction step comprises the Wittig reaction to give the 3-vinyl-substituted derivative, in which the reaction is carried out in methylene chloride/toluene/tetrahydrofuran at −78° C. The crude product is extracted by stirring with ethanol and recrystallized from methylene chloride/tert-butyl methyl ether or purified by chromatography. According to the method disclosed in WO 01/90111, the Wittig reaction is carried out at low temperatures of from −80 to −70° C. in a complex solvent mixture of methylene chloride, toluene and tetrahydrofuran. When the reaction is carried out on a production scale, this leads to considerable disadvantages, since regeneration of the process solvents is made difficult.
A disadvantage of the syntheses known from the prior art is that the compound of the general formula (2) or of the general formula (1) is produced via a multi-stage process which comprises complex synthesis steps and delivers poor overall yields. Furthermore, involved protective group operations are necessary.